Proteomics

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PTENa/b paradoxically promote carcinogenesis through WDR5-H3K4me3 axis

ABSTRACT: PTEN, a widely investigated tumor suppressor, has at least two longer translational variants, PTEN and . However, the regulation and precise roles of endogenous PTEN/ in tumorigenesis remain greatly unknown. Here we show that USP9X and FBXW11 selectively regulate the stability of PTEN/ but not PTEN proteins by deubiqitination and ubiquitination respectively. USP9X promotes and FBXW11 suppresses tumorigenesis mediated by PTEN/. In contrast to the current paradigm for PTEN as a tumor suppressor, PTEN/ promote tumorigenesis of cancer cells in a phosphatase-independent manner. Mechanistically, PTEN/ localized in the nucleus regulate expressions of tumor-promoting genes such as NOTCH3 in the similar way as the H3K4 presenter WDR5. Further, PTEN/ but not PTEN directly interact with WDR5 to promote trimethylation of H3K4 and maintain a tumor-promoting signature. Taken together, our results indicate that PTEN/ are a double-edged sword for carcinogenesis, suggesting that reinterpretation of the importance of PTEN gene in carcinogenesis is warranted.

INSTRUMENT(S): LTQ Orbitrap, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: ge mengkai  

LAB HEAD: Guo-Qiang Chen

PROVIDER: PXD013196 | Pride | 2019-11-14

REPOSITORIES: Pride

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Publications

PTENα and PTENβ promote carcinogenesis through WDR5 and H3K4 trimethylation.

Shen Shao-Ming SM   Zhang Cheng C   Ge Meng-Kai MK   Dong Shuang-Shu SS   Xia Li L   He Ping P   Zhang Na N   Ji Yan Y   Yang Shuo S   Yu Yun Y   Zheng Jun-Ke JK   Yu Jian-Xiu JX   Xia Qiang Q   Chen Guo-Qiang GQ  

Nature cell biology 20191104 11

PTENα and PTENβ are two longer translational variants of phosphatase and tensin homolog (PTEN) messenger RNA. Their expressional regulations and functions in carcinogenesis remain largely unknown. Here, we demonstrate that, in contrast with the well-established tumour-suppressive role of canonical PTEN, PTENα and PTENβ promote tumourigenesis by directly interacting with the histone H3 lysine 4 (H3K4) presenter WDR5 to promote H3K4 trimethylation and maintain a tumour-promoting signature. We also  ...[more]

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